Systems and methods for imaging a body region using implanted markers

ABSTRACT

Apparatus, systems, and methods are provided for localization of a region within a patient&#39;s body using markers implanted within the region. In an exemplary embodiment, a probe includes a distal end for placement against a surface of the region; one or more antennas for transmitting electromagnetic signals into and receiving reflected signals from the region; a light source for delivering light pulses into the region whereupon the markers modulate reflected signals. A processor of the probe processes the modulated reflected signals at one or more of the surface locations to determine marker locations within the region to obtain a reference frame, determine distance values corresponding to distances from the respective markers to the distal end at each of the surface locations, and determine coordinates of the surface locations relative to the reference frame to generate a three dimensional model of the body region.

RELATED APPLICATIONS

The present application claims priority to U.S. Provisional ApplicationNo. 62/931,059, filed on Nov. 5, 2019 and titled, “SYSTEMS AND METHODSFOR IMAGING A BODY REGION USING IMPLANTED MARKERS,” which is herebyincorporated by reference in its entirety.

TECHNICAL FIELD

The present disclosure relates to systems and methods for imaging aregion of a patient's body, e.g., by identifying and/or locating markersimplanted within the patient's body to generate a model of the region,e.g., in anticipation of and/or during surgical or other medicalprocedures, such as during lumpectomy procedures.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other features, aspects, and advantages of the presentdisclosure will become better understood with regard to the followingdescription, appended claims, and accompanying drawings where:

FIG. 1 shows an exemplary embodiment of a system for delivering andlocalizing a marker within a patient's body including a probe and adelivery device for implanting one or more markers within a patient'sbody.

FIG. 2 is block diagram depicting exemplary components of the probe ofFIG. 1.

FIG. 3 is a schematic showing the system of FIG. 1 using the probe toidentify and/or locate a plurality of markers that may be implantedwithin a patient's body.

FIGS. 4A-4C are perspective, side, and end views, respectively, of anexemplary probe that may be included in a system such that shown inFIGS. 1-2.

FIG. 4D is a detail of an antenna assembly that may be included in theprobe shown in FIGS. 4A-4C.

FIGS. 5A and 5B are top and side views, respectively, of an exemplaryembodiment of a marker for implantation within a patient's body.

FIG. 6 is an exemplary embodiment of a schematic of a circuit that maybe included in the marker of FIGS. 5A and 5B.

FIGS. 7A and 7B are schematics demonstrating operation of a switch ofthe circuit of FIG. 6.

FIGS. 8A and 8B are side views of a breast, showing a delivery devicebeing used to deliver a marker into tissue within the breast.

FIG. 9 is a side view of an exemplary embodiment of a probe localizing aplurality of markers implanted within a breast.

FIGS. 10A and 10B show a method for using localization of multiplemarkers implanted within a breast relative to the tip of the probeplaced against the skin to identify the location of the tip at multiplelocations on the breast to generate a three-dimensional model of thebreast.

FIG. 11 is a schematic showing an exemplary algorithm for generating acoordinate system using a plurality of markers implanted within a bodyregion.

FIGS. 12A and 12B show a system and method for generating athree-dimensional model of a breast using an external camera inconjunction with a probe that localizes a marker within the breast.

FIGS. 13A and 13B are side and end views of another exemplary embodimentof a probe including a single transmit antenna and a plurality ofreceive antennas to generate a three-dimensional model of a body region.

FIGS. 14A-14C show alternative configurations of an antenna assemblythat may be included in the probe of FIGS. 13A and 13B.

FIG. 15 shows the probe of FIGS. 13A and 13B placed against a patient'sbreast to obtain a reference frame from a plurality of markers implantedwithin the breast.

FIGS. 16A-16C show an exemplary method for determining the location of amarker using the probe of FIGS. 13A and 13B.

FIG. 17 illustrates an antenna placement template that may be used tocoordinate locations of multiple measurements taken by the probe.

FIG. 18 is a side view of an exemplary embodiment of a probe localizinga plurality of markers implanted within a breast.

FIG. 19 is a chart with three sets of distance values determined usingthe probe at locations based on the antenna placement template.

FIG. 20A-20C illustrate potential interfaces that may be used to displaythe coordinates for each marker.

DETAILED DESCRIPTION

Before a biopsy or surgical procedure to remove a lesion within abreast, e.g., during a lumpectomy procedure, the location of the lesionmust be identified. For example, mammography or ultrasound imaging maybe used to identify and/or confirm the location of the lesion before theprocedure. The resulting images may be used by a surgeon during theprocedure to identify the location of the lesion and guide the surgeon,e.g., during dissection to access and/or remove the lesion. However,such images are generally two dimensional and therefore provide onlylimited guidance for localization of the lesion since the breast and anylesion to be removed are three-dimensional structures. Further, suchimages may provide only limited guidance in determining a proper marginaround the lesion, i.e., defining a desired specimen volume to beremoved.

To facilitate localization, immediately before a procedure, a wire maybe inserted into the breast, e.g., via a needle, such that a tip of thewire is positioned at the location of the lesion. Once the wire ispositioned, it may be secured in place, e.g., using a bandage or tapeapplied to the patient's skin where the wire emerges from the breast.With the wire placed and secured in position, the patient may proceed tosurgery, e.g., to have a biopsy or lumpectomy performed.

One problem with using a wire for localization is that the wire may movebetween the time of placement and the surgical procedure. For example,if the wire is not secured sufficiently, the wire may move relative tothe tract used to access the lesion and consequently the tip maymisrepresent the location of the lesion. If this occurs, when thelocation is accessed and tissue removed, the lesion may not be fullyremoved and/or healthy tissue may be unnecessarily removed. In addition,during the procedure, the surgeon may merely estimate the location ofthe wire tip and lesion, e.g., based on mammograms or other imagesobtained during wire placement, and may proceed with dissection withoutany further guidance. Again, since such images are two dimensional, theymay provide limited guidance to localize the lesion being treated orremoved.

Alternatively, it has been suggested to place a radioactive seed toprovide localization during a procedure. For example, a needle may beintroduced through a breast into a lesion, and then a seed may bedeployed from the needle. The needle may be withdrawn, and the positionof the seed may be confirmed using mammography. During a subsequentsurgical procedure, a hand-held gamma probe may be placed over thebreast to identify a location overlying the seed. An incision may bemade and the probe may be used to guide excision of the seed and lesion.

Because the seed is delivered through a needle that is immediatelyremoved, there is risk that the seed may migrate within the patient'sbody between the time of placement and the surgical procedure. Thus,similar to using a localization wire, the seed may not accuratelyidentify the location of the lesion, particularly, since there is noexternal way to stabilize the seed once placed. Further, such gammaprobes may not provide desired precision in identifying the location ofthe seed, e.g., in three dimensions, and therefore may only providelimited guidance in localizing a lesion.

Accordingly, apparatus and methods for localization of lesions or otherbody structures in advance of and/or during surgical, diagnostic, orother medical procedures would be useful.

Embodiments herein are directed to systems and methods for imaging aregion of a patient's body, e.g., by identifying and/or locating markersimplanted within the patient's body to generate a model of the region.For example, the systems and methods herein may be used to generate athree-dimensional model of a body region of a patient using a pluralityof markers to obtain a reference frame, e.g., in anticipation of and/orduring surgical or other medical procedures, such as during lumpectomyprocedures.

In accordance with one embodiment, a probe is provided for localizationof a region within a patient's body using a plurality of markersimplanted within the region. The probe may include a housing including adistal end configured for placement against a surface of the regiontowards the markers, one or more antennas adjacent the distal end fortransmitting electromagnetic signals into a patient's body and receivingreflected signals from the patient's body, and a light source fordelivering light pulses into a patient's body synchronized with theelectromagnetic signals whereupon the markers modulate reflected signalsfrom the respective markers. In addition, a processor or controller ofthe probe is coupled to the one or more antennas and configured toprocess the modulated reflected signals from the markers at one or moreof the surface locations to determine marker locations within the regionto obtain a reference frame relative to the region; determine distancevalues corresponding to distances from the respective markers to thedistal end at each of the surface locations; and determine coordinatesof the surface locations relative to the reference frame to generate amodel of the body region. The model may then be presented on a display,e.g., showing the markers within the body region, to facilitate amedical procedure.

In accordance with still another embodiment, a system is provided for asystem is provided for localization of a region within a patient's bodythat includes a plurality of markers sized for implantation within aregion within a patient's body and a probe. Each marker may include anenergy converter configured to transform light pulses into electricalenergy; one or more elongate members coupled to a switch to provide oneor more antennas; and a circuit coupled to the energy converter andswitch to open and close the switch to modulate electromagnetic signalsreflected by the marker based at least in part on the light pulses. Theprobe may include a housing comprising a distal end configured forplacement against a surface of the region towards the markers; one ormore antennas adjacent the distal end for transmitting electromagneticsignals into a patient's body and receiving reflected signals from thepatient's body; a light source for delivering light pulses into apatient's body synchronized with the electromagnetic signals whereuponthe markers modulate reflected signals from the respective markers; anda processor coupled to the one or more antennas. The processor may beconfigured to process the modulated reflected signals from the markersat one or more of the surface locations to determine marker locationswithin the region to obtain a reference frame relative to the region;determine distance values corresponding to distances from the respectivemarkers to the distal end at each of the surface locations; anddetermine coordinates of the surface locations relative to the referenceframe to generate a model of the body region.

In accordance with still another embodiment, a method is provided forlocalization of a region within a patient's body using a plurality ofmarkers implanted within the region that includes placing a distal endof a probe sequentially against a plurality of surface locationsadjacent the region; at each of the surface locations, activating theprobe to transmit electromagnetic signals into the patient's body,receive reflected signals from the patient's body, and insynchronization with transmitting the electromagnetic signals, deliverlight pulses into the patient's body, whereupon the plurality of markersmodulate reflected signals from the respective markers; and a processorof the probe processes the modulated reflected signals from one or moreof the surface locations to determine marker locations within the regionto obtain a reference frame relative to the region and to determinedistance values corresponding to distances from the respective markersto the distal end at each of the surface locations, and the processordetermines coordinates of the surface locations relative to thereference frame to generate a model of the region.

In accordance with yet another embodiment, a method is provided forlocalization of a region within a patient's body that includesimplanting a plurality of markers within the region, e.g., to identify alesion therein; placing a distal end of a probe sequentially against aplurality of surface locations adjacent the region; and at each of thesurface locations, activating the probe to transmit electromagneticsignals into the patient's body, receive reflected signals from thepatient's body, and in synchronization with transmitting theelectromagnetic signals, deliver light pulses into the patient's body,whereupon the plurality of markers modulate reflected signals from therespective markers. A processor of the probe may process the modulatedreflected signals from one or more of the surface locations to determinemarker locations within the region to obtain a reference frame relativeto the region and to determine distance values corresponding todistances from the respective markers to the distal end at each of thesurface locations, and the processor may determine coordinates of thesurface locations relative to the reference frame to generate a threedimensional model of the region.

In accordance with another embodiment, a probe is provided forlocalization of a region within a patient's body using one or moremarkers implanted within the region, the probe including a housingcomprising a distal end including a substrate configured for placementagainst a surface of the region towards the markers; a transmit antennaon the substrate configured for transmitting electromagnetic signalsinto a patient's body; a plurality of receive antennas spaced apart fromone another on the substrate, each configured for receiving reflectedsignals from the patient's body; a light source for delivering lightpulses distally from the substrate into a patient's body synchronizedwith the electromagnetic signals whereupon the one or more markersmodulate reflected signals from the one or more markers; and a processorcoupled to the plurality of sets of receive antennas configured toprocess the modulated reflected signals from the one or more markers todetermine distance values corresponding to distances from the one ormore markers to respective sets of receive antennas, and determinecoordinates defining the spatial location of the one or more markersrelative to the distal end.

In accordance with still another embodiment, a system is provided forlocalization of a region within a patient's body that includes one ormore cameras for acquiring images of a body region of a patient's bodyto generate a model of the body region; and a probe. The probe mayinclude a housing comprising a distal end configured for placementagainst a surface of the region towards one or more markers implantedwithin the body region; one or more antennas adjacent the distal end fortransmitting electromagnetic signals into a patient's body and receivingreflected signals from the patient's body; a light source for deliveringlight pulses into a patient's body synchronized with the electromagneticsignals whereupon the markers modulate reflected signals from therespective markers; and a processor coupled to the one or more antennasconfigured to process modulated reflected signals from the one or moremarkers to determine distance values corresponding to distances fromrespective markers to the distal end; and determine coordinates of theone or more markers within the model of the body region.

Other aspects and features of the present disclosure will becomeapparent from consideration of the following description taken inconjunction with the accompanying drawings.

The components of the embodiments as generally described and illustratedin the figures herein can be arranged and designed in a wide variety ofdifferent configurations. Thus, the following more detailed descriptionof various embodiments, as represented in the figures, is not intendedto limit the scope of the present disclosure, but is merelyrepresentative of various embodiments. While various aspects of theembodiments are presented in drawings, the drawings are not necessarilydrawn to scale unless specifically indicated.

The phrase “coupled to” is broad enough to refer to any suitablecoupling or other form of interaction between two or more entities. Twocomponents may be coupled to each other even though they are not indirect contact with each other. For example, two components may becoupled to one another through an intermediate component. The phrases“attached to” or “attached directly to” refer to interaction between twoor more entities that are in direct contact with each other and/or areseparated from each other only by a fastener of any suitable variety(e.g., an adhesive).

The terms “proximal” and “distal” are opposite directional terms. Forexample, the distal end of a device or component is the end of thecomponent that is furthest from the practitioner during ordinary use.The proximal end refers to the opposite end, or the end nearest thepractitioner during ordinary use.

FIGS. 1-3 show an exemplary embodiment of a system 10 for localizationof a target tissue region within a patient's body, e.g., for identifyingand/or locating one or more markers 40 implanted within or adjacent atarget tissue region, such as a tumor, lesion, or other tissuestructure. In an exemplary embodiment, the system 10 may be used togenerate a three-dimensional model of a body region of a patient, e.g.,using a plurality of markers 40 as shown in FIG. 3, implanted with thebody region to provide a reference frame, in anticipation of and/orduring surgical or other medical procedures. For example, as shown inFIGS. 10A and 10B, a plurality of markers 40 may be implanted within abreast 90 for use during a biopsy or lumpectomy procedure, e.g., togenerate a model to facilitate localization of a lesion or other targettissue region and/or to facilitate dissection and/or removal of aspecimen from a breast 90, as described further elsewhere herein. Itshould be noted that, although the system 10 is described as beingparticularly useful in localization of breast lesions, the system 10 mayalso be used in localization of other objects in other regions of thebody, e.g., as described in the applications incorporated by referenceherein.

As shown in FIG. 1, the system 10 may include a delivery device 60carrying one or more targets, tags, or markers (one marker 40 shown), aprobe 20 for detecting and/or locating the marker 40 (or multiplemarkers 40(1)-40(N), e.g., the three markers shown in FIG. 3), and acontroller and/or display unit 38 coupled to the probe 20, e.g., usingone or more cables 36, generally similar to embodiments described inU.S. Publication Nos. 2011/0021888, 2014/0309522, 2016/0354177,2017/0252124, 2017/0319102, and 2018/0279907, U.S. application Ser. No.16/124,053, and U.S. provisional application Ser. No. 62/871,059, theentire disclosures of which are expressly incorporated by referenceherein.

The probe 20 is a portable device having electromagnetic signal emittingand receiving capabilities. In some embodiments, the probe 20 is anelongate handheld device including a first or proximal end 22 which maybe held by a user, and a second or distal end 24 intended to be placedagainst or adjacent tissue, e.g., a patient's skin or underlying tissue,defining a longitudinal axis 25 therebetween.

In some embodiments, the probe 20 includes one or more antennas 32, forreceiving and transmitting mounted or carried on an antenna assembly 30.For example, as shown in FIGS. 4A-4C, including one or more transmitantennas 32T and receive antennas 32R on a base 32, as described furtherbelow. In addition, the probe 20 includes a light transmitter, e.g., aplurality of light fibers 28 (shown in FIG. 4C), configured to transmitlight pulses 28 a into tissue contacted by the distal end 24, e.g.,generally along the longitudinal axis 25 into breast tissue 90, as shownin FIG. 9. The light fibers 28 may be coupled to a light source (notshown), e.g., by coupling 29 (shown in FIG. 9), such that light from thelight source passes through the light fibers 28 distally from the distalend 24 of the probe 20.

In some embodiments, the probe includes one antenna for receiving andtransmitting mounted or carried on the antenna assembly 30.

In an exemplary embodiment, the light source is an infrared lightsource, e.g., capable of delivering near infrared light between, forexample, eight hundred and nine hundred fifty nanometers (800-950 nm)wavelength. Optionally, the light fibers 28 may include one or lenses,filters, and the like (not shown), if desired, for example, to focus thelight transmitted by the probe 20 in a desired manner, e.g., in arelatively narrow beam extending substantially parallel to thelongitudinal axis 25, in a wider angle beam, and the like. In anotheroption, multiple light sources and/or filters may be provided to allowthe probe 20 to deliver light pulses in different narrow bands.Alternatively, one or more light sources, e.g., IR LEDs, may be providedon the distal end 24 instead of light fibers 28 to deliver the lightpulses 28 a.

The probe 20 may include a processor within the probe housing 21 and/ordisplay unit 38 including one or more circuits, signal generators,gates, and the like (not shown) needed to generate signals fortransmission by the transmit antenna(s) 32T and/or to process signalsreceived from the receive antenna(s) 32R. The components of theprocessor may include discrete components, solid state devices,programmable devices, software components, and the like, as desired.

FIG. 2 is a block diagram showing exemplary components of a controllerof the probe 20 (although, alternatively, some of the components may belocated within the controller/display unit 38 of FIG. 1). In the exampleshown, the probe 20 may include a signal generator 20 a, an amplifier 20b, an analog-to-digital (A/D) converter 20 c, and a digital signalprocessor (DSP) 20 d. The signal generator 20 a, e.g., a referenceoscillator, produces an oscillating signal, such as a square wavesignal, a triangular wave signal, or a sinusoidal signal.

For example, the probe 20 may include an impulse generator, e.g., apulse generator and/or pseudo noise generator (not shown), coupled tothe transmit antenna to generate transmit signals, and an impulsereceiver for receiving signals detected by the receive antenna. Theprobe 20 may include a micro-controller and a range gate control thatalternately activate the impulse generator and impulse receiver totransmit electromagnetic pulses, waves, or other signals via thetransmit antenna, and then receive any reflected electromagnetic signalsvia the receive antenna, e.g., similar to other embodiments herein.Exemplary signals that may be used include microwave, radio waves, suchas micro-impulse radar signals, e.g., in the ultralwide bandwidthregion.

In the example shown in FIG. 2, a square wave signal may be sent fromthe signal generator 20 a to the transmit antenna(s) 32T of the antennaassembly 30 of the probe 20. The antenna assembly may include a transmitantenna and a receive antenna. In some embodiments, the antenna elementsmay include a bowtie transmit antenna and a bowtie receive antenna withthe transmit antenna offset ninety degrees (90°) from the receiveantenna to define a Maltese cross antenna.

When the square wave signal passes through the transmit antenna(s) 32T,the transmit antenna(s) 32T may act as a band pass filter (“BPF”) andconvert the square wave signal to a series of pulses or other transmitsignals 34T. As such, the transmit signals 34T (shown in FIG. 3)transmitted by the probe 20 may include a series of pulses.Alternatively, the probe 20 may be configured to transmit continuouswave signals, e.g., similar to embodiments described in the referencesincorporated by reference herein.

The transmit signals 34T may be transmitted into the tissue andreflected from the implanted marker(s) 40, as represented by the receivesignals 34R shown in FIG. 3. Once the transmit signals 34T are reflectedfrom the marker(s) 40, the reflected signals (i.e., the receive signals34R) include a series of attenuated pulses (shown in FIG. 2).

As shown in FIGS. 2 and 3, the receive antenna(s) 32R of the antennaassembly 30 of the probe 20 may receive the receive signals 34R, whichmay be inputted into amplifier 20 b in order to amplify the gain of thepulses. The output of the amplifier 20 b may be inputted into an A/Dconverter 20 c in order to convert the amplified analog signal into adigital signal. The digital signals output from the A/D converter 20 cmay be inputted into a DSP 20 d for further processing. The DSP 20 d mayperform a number of processing functions including, but not limited to,calculating a difference in time from the time the transmit signals 34Twere sent to the time the receive signals 34R were received (propagationtime delay), determining the distance from the distal end 24 of theprobe 20 to the marker 40, determining the location of the marker 40relative to the distal end 24 of the probe 20, measuring the amplitudeof the receive signals 34R, and/or determining the direction the marker40 relative to the distal end 24 of the probe 20, e.g., as described inthe references incorporated by reference herein.

The probe 20 may be coupled to a display 38 a of the display unit 38,e.g., by cables 36, for displaying information to a user of the probe20, e.g., spatial or image data obtained via the antennas 32R and/orother output from the DSP 20 d. For example, FIG. 10B shows an exemplaryoutput that may be presented, including a three-dimensional model of themarkers within the body region, as described further elsewhere herein.As another example, FIGS. 10-11C show exemplary outputs that may bepresented.

Optionally, the probe 20 may include other features or components, suchas one or more user interfaces, memory, transmitters, receivers,connectors, cables, power sources, and the like (not shown). Forexample, the probe 20 may include one or more batteries or otherinternal power sources for operating the components of the probe 20.Alternatively, the probe 20 may include a cable, such as one of thecables 36, that may be coupled to an external power source, e.g.,standard AC power, for operating the components of the probe 20.

As shown in FIGS. 1 and 9, the internal components of the probe 20 maybe provided in an outer housing or casing 21 such that the probe 20 isself-contained, e.g., containing the components shown in FIGS. 4A-4D.For example, the casing 21 may be relatively small and portable, e.g.,such that the entire probe 20 may be held in a user's hand. Optionally,a portion of the probe 20 may be disposable, e.g., a portion adjacentthe distal end 24, or a disposable cover, sleeve, and the like (notshown) may be provided if desired, such that at least a proximal portionof the probe 20 may be reusable. Alternatively, the entire probe 20 maybe a disposable, single-use device while the display unit 38 may be usedduring multiple procedures by connecting a new probe 20 to the displayunit 38, which may remain out of the surgical field yet remainaccessible and/or visible, as desired. Additional information onconstruction and/or operation of the probe 20 may be found in thereferences incorporated by reference elsewhere herein.

Turning to FIGS. 4A-4D, exemplary internal components of the probe 20are shown (after removing the outer housing 21), e.g., including aninternal sleeve or housing 26 carrying the antenna assembly 30, and,optionally, shielding 37, on or within its distal end 26 b. Withparticular reference to FIG. 4D, the antenna assembly 30 includes a base32 including a substantially planar distal surface 32 a, e.g., extendingperpendicular to longitudinal axis 25, and a plurality of proximalplanar surfaces 32 b including antenna elements 32T, 32R. Alternatively,a single proximal planar surface (not shown) may be provided oppositethe distal surface 32 a including antenna elements, similar to the probe120 shown in FIGS. 13A-15 and described elsewhere herein, or in theembodiments in the references incorporated by reference herein.

The distal surface 32 a may be located at a distal-most location of thedistal end 24 of the probe 20, e.g., such that the distal surface 32 amay be placed directly against a body surface, e.g., a patient's skin,tissue surface, and the like (e.g., covered with a thin membrane orcover to prevent fluids from entering the probe and/or othercontamination). The base 32 may be formed from ceramic and/or othernonconductive material, e.g., having desired dielectric properties. Forexample, the base 32 may be formed from material having a dielectricconstant (permittivity) similar to the tissue type the probe is intendedto be used with, e.g., a dielectric constant similar to human breasttissue, skin, muscle, bone, fat or other tissue.

In the configuration shown in FIG. 4D, the antenna elements may includea pair of transmit antennas 32T and a pair receive antennas 32R arrangedin bowtie configurations on the proximal surfaces 32 b of the base 32,e.g., with the transmit antennas 32T offset ninety degrees) (90° fromthe receive antennas 32R to define a Maltese cross antenna. Each of theantenna elements 32T, 32R may be formed separately and then attached tothe corresponding proximal surfaces 32 b or may be deposited directlyonto the proximal surfaces 32 b. In an exemplary embodiment, the antennaelements 32T, 32R may be formed from silver film or other materialdeposited onto the proximal surfaces 32 b of the base 32.

Circuitry 35, e.g., a printed circuit board, flex circuit, and the like,may be coupled to the antennas 32T, 32R, e.g., including a PCB on whichare provided one or more transformers and/or connectors (not shown)coupled to the respective antenna elements 32T, 32R by appropriate leads35 a. As shown in FIGS. 4A and 4B, coaxial cables or other leads 35 bmay be coupled to connectors on the PCB to allow the antenna elements32T, 32R to be coupled to other components of the system, e.g., to causethe antenna elements 32T to transmit signals and/or to communicatereceived signals to other components of the system 10, similar to otherembodiments described herein.

As shown in FIGS. 4C and 4D, the base 32 also includes a plurality ofradial slots 33, e.g., a slot 33 between adjacent planar surfaces 32 b.The slots 33 may extend axially from the distal surface 32 a to theproximal surfaces 32 b to substantially isolate the antenna elements32T, 32R from one another by air within the slots 33, which may increasesensitivity, reduce crosstalk and/or other noise, and the like.Alternatively, the slots 33 may be filled with other insulatingmaterial, e.g., foam and the like (not shown), which may have a desiredrelatively low dielectric constant to substantially isolate the antennaelements 32T, 32R from one another. In addition, as shown in FIG. 4C,one or more light fibers or other light sources 28 may be positionedwithin one or more of the slots 33, e.g., to deliver light pulses beyondthe distal surface 32 a of the base 32, as described elsewhere herein.

Optionally, as shown in FIGS. 4A and 4B, the base 32 may be mountedwithin shielding 37, which may in turn, be coupled to the distal end 26b of the inner housing 26 (and/or the distal end 24 of the outer housing21), e.g., by one or more of bonding with adhesive, sonic welding,fusing, cooperating connectors (not shown), and the like, similar toembodiments in the references incorporated by reference herein. Theshielding 37 may have a length (i.e., along the axis 25) substantiallylonger than a thickness of the base 32 (i.e., the distance along theaxis 25 from the distal surface 32 a to a proximal end of the base 32).The distal surface 32 a of the base 32 may be substantially flush withthe distal end of the shielding 37 such that the distal surface 32 a maycontact tissue during use, as described elsewhere herein. Optionally, aMylar film or other relatively thin layer of material (not shown) may beprovided over the distal surface 32 a of the base 32 and/or theshielding 37, e.g., to prevent fluids or other material entering thetip, reduce contamination, and/or otherwise protect the tip of the probe20.

With continued reference to FIGS. 4A-4D, the proximal surfaces 32 b ofthe base 32 may be exposed to a region of air within the shielding 37.Because of the low dielectric constant of air (e.g., close to one (1)),the air provides a dielectric or impedance mismatch with the material ofthe base such the transmission from the transmit antenna 32T is focuseddistally, i.e., towards the tissue contacted by the base 32. With thematerial of the base 32 chosen to substantially match the dielectricconstant of tissue, the depth of transmission into the tissue may beenhanced. The air behind the base 32 may minimize lost energy that wouldotherwise be emitted by the transmit antenna 32T away from the tissue.The air behind the base 32 within the shielding 37 may also minimizecrosstalk, noise and/or may otherwise enhance operation of the probe 20.

Turning to FIGS. 5A and 5B, an exemplary embodiment of a passive markeror tag 40 is shown that may be implanted within a patient's body, suchas within a breast 90, e.g., as shown in FIG. 9. Generally, the marker40 includes an electronics package 42 coupled to a pair of wires orantennas 44. In an exemplary embodiment, each wire 44 may be an elongatemember, e.g., a solid or hollow structure having a diameter or othermaximum cross-section between about half and two millimeters (0.5-2 mm)and a length between about one and ten millimeters (1.0-10 mm). Thewires 44 may be formed from elastic or superelastic material and/or fromshape memory material, e.g., stainless steel, Nitinol, and the like,such that the wires 44 are biased to a predetermined shape when deployedwithin tissue, but may be elastically deformed, e.g., to facilitatedelivery, as explained elsewhere herein. Alternatively, the wires 44 maybe substantially rigid such that the marker 40 remains in asubstantially fixed, e.g., linear or curved, shape. As describedelsewhere herein, the wires 44 may act as antennas and/or otherwisecooperate with electrical components within the electronics package 42.

As shown in FIGS. 5A and 5B, the wires 44 may be biased to assume asubstantially linear configuration, e.g., such that the wires 44 extendsubstantially parallel to a longitudinal axis 48 of the marker 40.Optionally, one or both wires 44 may be offset from the longitudinalaxis 48, which may enhance loading the marker 40 within a deliverydevice (not shown), as described elsewhere herein. Optionally, the wires44 may carry one or more beads or other elements (not shown), e.g.,similar to embodiments described in the references incorporated byreference herein.

As shown, each wire 44 may include a first end 44 a coupled to a printedcircuit board (PCB) or other circuit 50 within the package 42 and asecond free end 44 b terminating in an enlarged and/or rounded tip 45.Optionally, the first ends 44 a may include one or more bends, e.g., tofacilitate coupling the first ends 44 a to the circuit 50 and/or suchthat the wires 44 extend tangentially from opposite sides of the package42. Alternatively, the wires 44 may be biased to assume a curvilinear orother configuration, e.g., a helical, serpentine or other curved shape,around the longitudinal axis 48. For example, the wires 44 may be formedfrom elastic or superelastic material that is shape set such that thewires 44 are biased to the helical configuration shown, yet may beresiliently straightened to a substantially linear configuration, e.g.,to facilitate loading the marker 40 into a delivery device and/orotherwise introducing the marker 40 into a patient's body, e.g., asdescribed in the applications incorporated by reference herein.

With additional reference to FIG. 6, the marker 40 may include one ormore circuits or other electrical components 50 encased or embedded inthe electronics package 42 and configured to modulate incident signalsfrom the probe 20. In an exemplary embodiment, a semiconductor chip,print circuit board (PCB), and/or other circuit 50 may be carried in thepackage 42 that includes a voltage or power source or other power orenergy converter 52, a switch 54 that may be opened and closed when theenergy converter 52 generate electrical energy, and an Electro StaticDischarge (ESD) protection device 58.

In an exemplary embodiment, the energy converter 52 includes a pluralityof photosensitive diodes capable of transforming incident light (e.g.,infrared light) striking them into electrical energy (e.g., apredetermined minimum voltage). As shown, multiple pairs of diodes 52may be connected in series, which may be arranged orthogonally to oneanother spatially within the package 42. The package 42 may be at leastpartially transparent or the diodes 52 may be exposed such that lightdirected towards the package 42 may be received by the diodes 52.

In the embodiment shown in FIG. 6, the switch 54 may be a field effecttransistor (FET), e.g., a junction field effect transistor (JFET), withone end of the diodes 52 coupled to the gate (G) and the other coupledto the source (S), with a resistor 56 coupled between the gate (G) andthe source (S), e.g., to discharge the diodes 52 when there is no IRlight. In an exemplary embodiment, the switch 54 may include anenhancement mode pseudomorphic high electron mobility transistor(E-pHEMT), such as a VMMK-1225 manufactured by Avago Technologies USInc., and the resistor 56 may be a three mega-Ohm (3MΩ) resistor. In analternative embodiment, the switch 54 may be a Schottky diode coupled tothe diodes 52 (or other voltage source), e.g., with opposite ends of thediode coupled to the wires 44.

Also as shown, the source (S) of the switch 54 may be electricallycoupled to one of the wires 44 and the drain (D) may be coupled to theother wire 44, e.g., such that the wires 44 provide an antenna for themarker 40. For example, the components of the circuit 50 may be mountedwithin the package 52 such that the components are electrically isolatedfrom one another other than as coupled in the schematic of FIG. 6. Thewires 44 may be bonded or otherwise attached to the package 52 such thatends of the wires 44 are electrically coupled to the switch 54 as shown.

Each diode 52 may be capable of generating sufficient voltage (e.g.,about a half Volt (0.5 V)) when exposed to light to open and close theswitch 54 when there is little or no load (i.e., current draw). Sincethe circuit 50 is intended to be merely modulate signals from the probe1020, little or no current is needed, and so the power required from thediodes 52 (and consequently from the probe 1020) may be minimal, therebyreducing power demands of the marker 40 and probe 1020.

With additional reference to FIGS. 7A and 7B, light intermittentlystriking the diodes 52 may generate a voltage across the gate (G) andsource (S) to provide a control signal that may open and close theswitch 54. For example, FIG. 7A shows the switch 54 in the openconfiguration when infrared light is absent, while FIG. 7B shows theswitch 54 in the closed configuration when infrared light 70 strikes thediodes 52, thereby connecting both wires 44 together. Thus, the resultis that the marker 40 provides a passive tag that includes what equatesto a high-frequency switch in the middle of the marker 40. By being ableto change the switch 54 from closed to open, the reflection propertiesof the antenna provided by the wires 44 may be changed significantly.

Specifically, the marker 40 is made to periodically change its structurebetween two form factors, e.g., the reflectors shown in FIGS. 7A and 7B.For example, as described further elsewhere herein, digital signalprocessing of the received signals using ultra-wideband (UWB) radar usessynchronous detection of the signal modulated with marker switchingfrequency. This significantly increases the signal-to-noise (SNR) on themarker signal because other contaminating signals remain unchangedwithin the modulation period. To provide a mechanism for a synchronousdetector, the marker switching process is controlled in the probe 20 byilluminating breast tissue with near infrared (IR) light pulses that arereceived by the marker 40.

Switching of the marker reflective form-factor is controlled with theset of diodes 52 operating in photovoltaic mode. When the diodes 52receive light from the probe 102 (represented by arrows 70 in FIG. 7B),the diodes 52 generate voltage that is applied between the gate (G) andsource (S) of the switch 54, which closes and connects together thedrain (D) and source (S) making both antenna wires 44 connectedtogether, as shown in FIG. 7B. When the light is off, the switch 54 isopen and the drain (D) and source (S) are electrically disconnected, asshown in FIG. 7A.

In addition, the markers may include one or more features to facilitateidentifying and/or distinguishing individual markers when multiplemarkers are implanted within a body region, e.g., to allow the probe 20to simultaneously or sequentially identify and localize each of themarkers. For example, in one embodiment, a plurality of markers may beprovided, with each marker including a clock circuit or block (notshown) coupled to the diodes 52 and a sequence generator (also notshown) coupled to the clock circuit and the switch 54 to generate a codesequence to open and close the switch 54 to modulate signals reflectedby the marker 40 back to the probe 20 based on the code sequence. Thesequence generator of each marker 40 may be pre-programmed such that thecode sequences generated by the sequence generators are orthogonal toone another, i.e., the sequence generators may open and close therespective switches 54, based on the light pulses from the light source28 of the probe 20, to modulate the reflective properties of the markers40 differently from one another. The probe 20 may be configured toanalyze the reflected signals to identify and locate each of the markers40 substantially simultaneously based on the resulting modulation in thereflected signals received by the probe 20, e.g., as described in U.S.application Serial No. Ser. No. 16/124,053 incorporated by referenceherein.

In addition or alternatively, the package 42 and/or the diodes 52 mayinclude one or more coatings and/or filters, e.g., to allow the probe 20to communicate individually, e.g., sequentially, within individualmarkers, similar to markers disclosed in U.S. Publication Nos.2017/0252124 and 2017/0319102, incorporated by reference herein. Forexample, the probe 20 may be capable of delivering separate narrow bandsof infrared light and the markers may include filters (not shown) suchthat individual markers may only receive respective narrow bands,thereby allowing the probe 20 to modulate and identify, individualmarkers.

Alternatively, the markers may include processors (not shown) thatanalyze light pulses from the probe 20 such that the processors mayidentify commands from the probe 20, e.g., to modulate individualmarkers. In this manner, the probe 20 may be able to activate and/ormodulate individual markers such that the probe 20 may identify and/orlocate the markers sequentially by sending commands in the light pulsesto activate individual markers in a desired sequence, e.g., as describedin the references incorporated by reference herein.

Optionally, in embodiments where individual markers 40 are localizedsequentially, the system may provide one or more outputs to identifywhich marker is currently being localized. For example, in the display38 a shown in FIG. 1, the bar or other output of an active marker may bedistinguished from the other dormant markers, e.g., by changing a colorof the output, e.g., distance bar or identifier, and the like. Inaddition or alternatively, a speaker may generate a different output,e.g., a different pitch, tone, or other sound, to identify the activemarker and/or otherwise distinguish it from dormant markers duringsequential localization.

Returning to FIGS. 1-3 and with additional reference to FIGS. 9, 10A,and 10B, the system 10, e.g., including the probe 20 and implantedmarkers 40, may be used to generate a three-dimensional model 90′ of abody region of a patient, e.g., breast 90, based on absolute or relativelocations of the markers 40, e.g., in anticipation of and/or during asurgical or other medical procedure. As shown in FIGS. 10A and 10B, themodel 90′ may be presented on a display 38 a, e.g., to facilitatelocalization of a lesion or other target tissue region within a breast90 and/or to facilitate dissection and/or removal of a specimen from thebreast 90, e.g., before and/or during a lumpectomy procedure.

FIGS. 8A and 8B illustrate a delivery device 60 being used to deliver amarker 40 into tissue within the breast tissue 90. As shown, thedelivery device 60 may include a lumen 62 and a plunger 68. The plunger68 may include a piston that extends into the lumen 62 and is slidablewithin the lumen 62. To introduce the marker 40 or markers within thebreast tissue 90, the marker may be positioned in the lumen 62 and thelumen may be inserted into the tissue. The plunger 68 may be advanced tocause the piston to push the marker(s) 40 from the lumen 62.

Before a procedure, a target tissue region, e.g., a tumor or otherlesion, may be identified using conventional methods. For example, alesion (not shown) within a breast 90 may be identified, e.g., usingmammography and/or other imaging, and a decision may be made to removethe lesion. One or more (e.g., three) markers 40 may be implanted withinthe breast 90 within or adjacent the lesion, as shown in FIG. 9, e.g.,using a needle or other delivery device, such as the delivery device 60shown in FIGS. 8A and 8B, as described further in the referencesincorporated by reference herein.

For example, the markers 40 may be implanted within the breast 90 in athree dimensional array surrounding the lesion or otherwise spaced apartfrom one another and the lesion, e.g., to define a desired margin orvolume, e.g., of a target specimen for removal around the lesion. Oncethe markers 40 are implanted, a model may be generated at any time afterimplanting the markers 40, e.g., immediately after implanting themarkers 40 to facilitate planning a procedure. In addition oralternatively, the model may generated immediately before the procedure,e.g., within the surgical setting for use by the surgeon to monitordissection and/or removal of a specimen during the procedure.

Generally, as shown in FIGS. 10A and 10B, the model 90′ of the breast 90may be presented on the display 38 a, which may also includerepresentations of the markers 40′ and/or probe 20.′ Presenting such amodel 90′ on a display 38 a during the procedure may facilitate asurgeon identifying the location of the markers 40 within the breast 90and thereby, identify the location of the lesion within the breast 90,e.g., relative to the distal end 24 of the probe 20, which may be usedby the surgeon during the lumpectomy procedure to identify a path fordissection and/or removal of the specimen, e.g., including the lesionand markers 40.

In an exemplary method for generating the model 90′ (once the markers 40are implanted), as shown in FIGS. 9 and 10A, the distal end 24 of theprobe 20 may be placed in contact with or adjacent the patient's skin,e.g., generally above the lesion, and/or otherwise aimed generallytowards the lesion and markers 40, and activated to determine a spatialrelationship between the markers 40 and the distal end 24 of the probe20. The probe 20 may then be moved to one or more additional surfacelocations, e.g., to obtain a reference frame and/or generate the model90′.

For example, initially, the distal end 24 of the probe 20 may be placedagainst the patient's skin (or other surface) at a first surfacelocation 92, e.g., as shown in FIG. 10A, and the probe 20 may beactivated. As described elsewhere herein, signals from the antenna(s)32T of the probe 20 may be delivered along with pulsed light from thelight source to cause the switches 54 to open and close as the markers40 receive and reflect signals back to the probe 20. The reflectedsignals from the two states (switches 54 open and closed) may besubtracted from one another, substantially eliminated other noise, andallowing the probe 20 to identify and/or locate the markers 40. Theprobe 20 may acquire signals from the markers 40 substantiallysimultaneously, e.g., using orthogonal code sequences, or sequentiallyby activating and/or polling the markers 40 sequentially, as describedelsewhere herein and in the references incorporated by reference herein.

The processor of the probe 20 may then identify and/or localize themarkers 40 based at least in part on the reflected signals. For example,based on propagation time delay between the transmitted signals 34T andreceived reflected signals 34R, distances d1, d2, d3 may be determinedfrom the markers 40 to the distal end 24, e.g., substantiallysimultaneously or sequentially, thereby providing distances from themarkers 40 to the distal end 24 (and consequently to the first surfacelocation 92 on the breast 90, as described further below). Optionally,the display 38 a may present information to the user related to thelocation of the markers 40 relative to the probe 20 based on the currentlocation of the distal end 24. For example, as shown in FIG. 1, thedisplay 38 a may include a readout on a portion thereof providingdistances from each of the markers 40 to the distal end 24 of the probe20. The distance information may be displayed as a numerical valuerepresenting the distance in units of length, such as in inches (in.) orcentimeters (cm).

The probe 20 may then be moved to a second location (not shown), e.g.,by sliding the distal end 24 along the patient's skin or lifting andmoving the distal end 24 for a desired distance from the first location92. The markers 40 may then again be identified and localized, e.g., toprovide distance information from the markers 40 to the distal end 24 atthe second location. Optionally, the probe 20 may be moved one or moreadditional times to acquire distance information from one or moreadditional locations.

Based on at least some of the distance information, the processor of theprobe 20 may obtain a reference frame, e.g., a three-dimensional x-y-zor other orthogonal reference frame, based on the locations of themarkers 40 within the breast 90. Thus, the reference frame may be fixedrelative to the breast and its associated structures, e.g., theoverlying skin.

Once the reference frame is established, the processor may generate themodel 90,′ e.g., by using trilateration, i.e., the distances d1-d3 fromthe markers 40 to the respective surface locations where the distanceswere acquired. For example, for the first location 92 shown in FIG. 10A,the processor may use the distances d1-d3 to determine an x-y-zcoordinate location of the first location 92. The processor may then mapthis on the model to identify the first location as represented bylocation 92′ in the display 38 a of FIG. 10A since the distances d1-d3may map to a unique location relative to the markers 40. This processmay be repeated for each of the surface locations to identify multiplelocations of the patient's skin. Once sufficient samples have beentaken, the processor may predict the surface of the breast 90 andpresent the resulting model 90′ on the display 38 a, e.g., as shown inFIG. 10B. The number of samples to generate the model 90′ may be basedthe size of the surface of the body region, e.g., breast 90, and/or thedesired granularity of the model 90′ to be displayed.

Once the model 90′ has been constructed, the processor may identify thecurrent location of the distal end 24 of the probe at any time and thenadd a representation of the probe 20′ to the model 90′, as shown in FIG.10A. Using this presentation, the surgeon may be able to observe in realtime the location of the distal 24 of the probe 20 relative to themarkers 40, and therefore, relative to the lesion, simply by observingthe model 90′ and the corresponding representations for the distal end24′ and the markers 40.″ For example, based on this information, thesurgeon may decide on the shortest and/or easiest path to the lesion,create an incision at a desired location in the patient's skin anddissect intervening tissue to a desired depth, e.g., corresponding to atarget margin around the lesion is reached. At any time, the distal end24 of the probe 20 may be inserted into the incision and/or otherwiseplaced against tissue to confirm the location of the markers 40 andlesion. Using this information, a tissue specimen may be excised orotherwise removed using conventional lumpectomy procedures, e.g., withthe markers 40 defining the desired margin or volume, and/or remainingwithin the removed specimen. In addition, if for some reason a bodyregion that has already been modeled has moved, e.g., if the patientmoves or is reoriented, at any time, the surgeon or other user, maygenerate a new model simply by repeating the process using the probe tolocalized the markers within the region.

Turning to FIG. 11, an exemplary algorithm will now be described, whichmay be used to obtain a reference frame and/or generate a model bylocalizing a plurality of markers implanted within a tissue structure,e.g., by simultaneously measuring the propagation time delays betweenthe radar antenna (i.e., the distal end 24 of the probe 20, not shown)and individual markers within a group of implanted markers. The markersmay be distinguished using preprogrammed orthogonal modulation codes,enable the probe to evaluate the distances to the markers from multiplelocations substantially simultaneously.

Calculations of the markers and probe locations from distancemeasurements may be performed using known methods of computationalgeometry and geometry algebra dealing with distance geometry problems.Various methods for solving distance geometry problems have beendeveloped for visualization of graphs given by set of nodes and lengthsof edges connecting them. Such types of problems frequently occur inpresentation and analysis of network structures, in molecular physics,robotics and other fields (see, for example a review by L. Liberti et al“Euclidian Distance Geometry and Applications” SIAM Review, 2014, Vol.56, No 1, pp. 3-69, the entire disclosure of which is expresslyincorporated by reference herein). Many different methods developed fordistance geometry problems may be applicable to the systems and methodherein.

With continued reference to FIG. 1, consider multiples markers O_(l),l=1 . . . N, placed in breast tissue to indicate the location of atumor, for the case of four markers, i.e., case N=4. Radar placed on thesurface of the breast at point S_(k) can evaluate a set of distancesd_(kl)=dist{S_(k), O_(l)}, l=1 . . . N to each marker O_(l) usingsimultaneous measurements of round-trip propagation times for eachmarker. To achieve the simultaneous measurements of the propagationtimes, each marker is configured to reflect radar signals with a presetcode of reflected modulation, enabling radar to distinguish the markerechoes in the received signals by using one of the methods of codedivision multiplexing, for example, those disclosed in U.S. applicationSer. No. 16/124,053, incorporated by reference herein. FIG. 11illustrates the geometry (a graph) of a single measurement and a methodfor selection of the reference coordinate systems (x, y, z) linked withthe markers. The coordinate system maybe defined using positions ofspecific markers, for example, where location of O₁ defines the originof the coordinate system, line connecting O₁ and O₂ the x-axis. Thereflectors O₁ and O₂ together with one of the remaining reflector, e.g.O₃, can define the (x, y) plane, i.e., z=0. Therefore, the coordinatesof the preselected markers defining the reference coordinate system willbe O₁(0,0,0), O₂(x₂, 0,0) and O₃(x₃, y₃, 0). Assuming that eachmeasurement provides N distance values d_(kl)=dist{S_(k), O_(l)}, l=1 .. . N, for M measurements at different locations, S_(k),k=1 . . . M onewill have MN distances given by the following set of equations

d _(kl)=√{square root over (({tilde over (x)} _(k) −x _(l))²+({tildeover (y)} _(k) −y _(l))²+({tilde over (z)} _(k) −z _(l))₂)}, k=1 . . .M, l=1 . . . N,  (1)

where variables marked with bar corresponds to (x, y, z)-coordinates ofS_(k) points. The number of equations in system (1) is given by thenumber of distance measurements and equals to MN, while the number ofunknown variables equals to 3N+3M−6. Here the last term, −6, is due tothe use of known coordinates for preselected reflectors O₁, O₂ and O₃ in3D space. To find all unknown coordinates for reflectors O₁,l=2 . . . Nand radar positions S_(k),k=1 . . . M, the number of equations should beequal or greater than the number of unknowns. Therefore, the number ofreflectors N and measurement sites M with simultaneous measurements ofdistances to all reflectors should satisfy the following condition

3N+3M−6≤MN,  (2)

which can be rewritten as

$M \geq \frac{3( {N - 2} )}{( {N - 3} )}$

Taking into account that setup of reference coordinate system in 3Dspace requires at least three reflectors (N≥3), the minimal number ofreflectors suited in this method is N=4 and, therefore, the minimalnumber of required measurements is M=6.

Since the systems of distance equations (1) consists of quadraticequations with multiple sets of solutions, an additional analysis isneeded to select the right solution set that satisfy the configurationof reflectors and measurement points. Use of additional constraintsbased on the expected configuration of reflectors and position ofmeasuring points may be required for such selection.

From the viewpoint of graph theory, the considered structure of nodes, Nand M, with the corresponding edges d_(kl) computed as (1) form abipartite graph in Euclidian space of dimension d=3. It is known that agraph containing n nodes will form a rigid framework in the space ofdimension d if the number of edges equals or more than (see for example,B. Hendrickson, “Conditions for Unique Graph Realizations”, SIAM J.Comput. 1992, Vol. 21, No. 1, pp. 65-84), the entire disclosure of whichis expressly incorporated by reference herein).

$\begin{matrix}{{{nd} - {{d( {d + 1} )}/2}},} & {{{if}\mspace{14mu} n} \geq {d.}} \\{{{n( {n - 1} )}/2},} & {{otherwise}.}\end{matrix}$

In the present case, n=N+M, d=3 and n≥d. Therefore, minimum number ofedges (i.e., the minimum number of measured distances, d_(kl)) should be3n−6=3N+3M−6 or, in the present case of bipartite graph, containing NMedges, this condition is equivalent to the condition (2) that guaranteethe matching the number of unknowns to the distance equations (1).

A possible approach to the solution of position problem is to use one ofthe known point fitting approach to fine locations of all O_(l) andS_(k) points. For example, this can be done by minimization of errors inthe fitting node locations (O_(l) and S_(k)) for a given set ofdistances between them. Such an error can be defined as

E=Σ _(k=1) ^(M)Σ_(l=1) ^(N)(d _(kl)−√{square root over (({tilde over(x)} _(k) −x _(l))²+({tilde over (y)} _(k) −y _(l))²+({tilde over (z)}_(k) −z _(l))²))}²

where x₁=0, Y₁=0, z₁=0, y₂=0, z₂=0 and z₃=0 are fixed values. The valueof E approaches zero when the all coordinates of the points (O_(l) andS_(k)) form a graph that fits to all measured distances d_(kl), for k=1. . . M, l=1 . . . N. By construction, the E is a positively definedfunction that can be used as a cost function. Other types of costfunctions known in the literature can be constructed for evaluation oftotal error. Various known methods of optimization can be used to findthe minimum of such a cost function that will correspond to the solutionfor the nodes (O_(l) and S_(k)) locations.

Another approach to solving this localization problem is to use methodsof spring embedders and force directed graph-drawing algorithms. In thisapproach, edges are considered as springs of lengths d_(kl) connectingthe corresponding nodes and the cost function E represents the totalpotential energy of the spring system. Force between the nodes producedby the springs tends to place the nodes in the positions where distancebetween the nodes equal to the lengths of the unloaded springs andtherefore the measured distances d_(kl). Various algorithms for suchcomputation of the graph realization is discussed in the literature,see, for example, S. G. Kobourov, Spring Embedders and Force DirectedGraph Drawing Algorithms, arXiv:1201.3011v1 [cs.CG] 14 Jan. 2012, theentire disclosure of which is expressly incorporated by referenceherein.

Turning to FIGS. 12A and 12B, another system 110 is shown for generatinga model of a body region, such as a breast 90. Generally, similar toother embodiments herein, the system 110 includes a probe 20, e.g.,including a processor and display 38 a (along with other componentssimilar to other probes 20 herein) and one or more markers 40 that maybe implanted within the breast 90 (one marker 40 shown), e.g., toidentify the location of a lesion. Unlike previous embodiments, thesystem 110 also includes one or more external cameras, e.g., 3D camera112, which may be mounted or otherwise fixed relative to itssurroundings, e.g., fixed relative to a bed on which a patient may lieand/or relative to an operating room or other setting within which thepatient will be presented to generate the model. The camera 112 may becoupled to a 3D image processing module 114, which may be a separatedevice or may be included in the controller 20 coupled to the probe 20.

During use, the camera 112 may acquire one or more two-dimensional orthree-dimensional images of the body region, e.g., breast 90, and theprocessing module 114 may process the image(s) to generate thethree-dimensional model 90′, which may be presented on display 38 aand/or stored in memory of the processing module 114 or controller 38.

The probe 20 may then be used to localize the marker(s) 40 implantedwithin the breast 90, e.g., by placing the distal end 24 against thepatient's skin and activating the probe 20. For example, electromagneticsignals, e.g., ultra-wide band radar signals, from the probe 20 may bedelivered along with pulsed light to cause a switch (not shown) of themarker 40 to open and close to modulate reflected signals from themarker 40, allowing the probe 20 to identify and/or locate the marker40, e.g., to determine a distance d from the marker 40 to the distal end24, as shown in FIG. 12B.

Simultaneously, the camera 112 may acquire one or more images of thebreast 90 and probe 20. The processing module 114 may process theimage(s) to identify the location of the distal end 24 of the proberelative to the breast 90, e.g., to identify the surface location on thepatient's skin where the distal end 24 is contacting the breast 90. Theprocessing module may then correlate the identified surface location andthe distance d to identify the location of the marker 40 within thebreast, which may then be added to the model 90′ (not shown). Forexample, the location of the marker 40 and the distal end 24 of theprobe 20 may then be used to guide a surgeon during the procedure, e.g.,to dissect breast tissue to remove the lesion. Optionally, multiplemarkers (not shown) may be implanted to surround the lesion and/ordefine a desired margin or volume, similar to other embodiments herein.

In another option, the probe 20 may include one or more sensors, e.g., acompass, magnetometer, and the like, to provide an orientation of theprobe 20, e.g., such that a direction of the distal end 24 into thebreast 90 may be determined to facilitate identifying the location ofthe marker 40 within the breast 90, e.g., to enhance the resultingthree-dimensional model 90.′

Turning now to FIGS. 13A-15, another exemplary embodiment of a probe 120is shown that may be used to identify and/or localize one or moremarkers within a body region, e.g. markers 40 implanted within breast 90shown in FIG. 15. Generally, the probe 120 includes components similarto other embodiments herein, e.g., including a housing 121 having adistal end 124 including a substrate 132 having a distal surface 132 aconfigured for placement against a body surface, e.g., the patient'sskin of the breast 90 shown in FIG. 15 towards the markers 40. The probealso includes an antenna assembly, e.g., including one or more transmitand receive antenna elements on a proximal surface 132 b of thesubstrate 132, and one or more light sources 128, e.g., coupled to acontroller and/or display unit (now shown), similar to other embodimentsherein.

Unlike previous embodiments, the probe 120 includes a single transmitantenna 132T, e.g., including a pair of bowtie antenna elements, on theproximal surface 132 b of the substrate 132, a plurality of receiveantennas 132R, each including a pair of bowtie antenna elements, spacedapart from one another on the proximal surface 132 b of the substrate132. Thus, the transmit antenna 132T may be configured for transmittingelectromagnetic signals, e.g., ultra-wide band radar signals, into apatient's body along with pulsed light from the light source 128 tocause a switch (not shown) of each marker 40 to open and close tomodulate reflected signals from each marker 40. Each receive antenna132R may be configured for receiving reflected signals from thepatient's body independent of the others, and a processor of the probe120 may process the modulated reflected signals to identify and/orlocate each marker 40, e.g., to determine a distance from each marker 40to the respective receive antennas 132R.

Given that the receive antennas 132R are spaced apart from one another,the distance from each receive antenna 132R to each marker 40 isdifferent and, consequently, the propagation time delay from thetransmit signals to the time the receive signals are received by eachreceive antenna 132R will be different. The processor may use thedifferences in the time delay and resulting distance dimension toperform trilateration and determine the spatial relationship of eachmarker 40 relative to the distal end 24, e.g., to determine an x-y-zcoordinate location of each marker 40. This spatial relationship may bemapped to a model generated by the system, e.g., similar to otherembodiments herein, to allow a surgeon or other user to observe thelocation of the marker(s) relative to the body region using the model(including representations of each marker) presented on a display.

If multiple markers 40 are implanted within the body region, as shown inFIG. 15, the processor may identify and/or localize each markersimultaneously, e.g., using orthogonal code sequences, or sequentially,e.g., using filters and/or bit commands, similar to other embodimentsherein. Alternatively, the probe 120 may be used to identify andlocalize a single marker implanted within the body region and provide athree-dimensional coordinate for the marker, which may be incorporatedinto any of the models described herein.

In the embodiment shown in FIG. 14A, the probe 120 includes a transmitantenna 132T located at the center of the substrate 132 and threeorthogonally oriented receive antennas 132R positioned evenly around thetransmit antenna 132T. Alternatively, as shown in FIG. 14B, a receiveantenna 132R′ may be mounted at the center with the transmit antenna132T′ with three additional receive antennas 132R′ positioned evenlyaround the central antenna. In a further alternative, shown in FIG. 14C,the probe 120″ may include a transmit antenna 132T″ located at thecenter of the substrate 132 “and four orthogonally oriented receiveantennas 132R” positioned evenly around the transmit antenna 132T.″ Itwill be appreciated that other arrangements may be provided, e.g.,including at least two receive antennas spaced apart from one another toprovide different propagation time delays and resulting distancemeasurements to each marker being localized.

Turning to FIGS. 16A-16C, an exemplary method is shown that may be usedto determine the three-dimensional location of a marker M relative to aprobe including a central transmit antenna Tx, and four receive antennasRx, spaced apart from the transmit antenna by distance “d”, e.g.,similar to the configuration of the probe 120″ shown in FIG. 14C. Inthis example, the reference frame used to determine the location of themarker M is centered on the transmit antenna Tx with the x axis alignedwith a first pair of the receive antennas Rx_(xL), Rx_(xR), on oppositesides of the transmit antenna T_(x), and the y axis aligned with anorthogonal second pair of receive antennas Rx_(yL), Rx_(yR), as shown inFIGS. 16A and 16B.

As with other embodiments herein, the transmit antenna T_(x) maytransmit signals, and the receive antennas Rx may receive signalsreflected by the marker M (e.g., radar echo), and a processor mayanalyze the received signals to determine propagation distances for thepaths from the transmit antenna Tx to each of the receive antennas Rx.For example, for the receive antennas Rx_(xL), Rx_(xR), the propagationdistances L_(x) and R_(x) may be determined and for the receive antennasRx_(yL), Rx_(yR), the propagation distances L_(y) and R_(y) may bedetermined, from the received signals.

As shown in FIG. 16C, the propagation distance L along the x axiscorresponds to distances c+a and propagation distance R corresponds toc+b (the propagation distances along the y axis are determined in asimilar manner). Given the geometry, the distances a, b, c may bedetermined as:

c=√{square root over (r ² +x ²)}

a=√{square root over (r ²+(x+d)²)}

b=√{square root over (r ²+(x−d)²)}

Thus, the propagation distances can be formulated as:

L=c+a=√{square root over (r ² +x ²)}+√{square root over (r ²+(x+d)²)}

R=c+b=√{square root over (r ² +x ²)}+√{square root over (r ²+(x−d)²)}

These equations may then be solved for x, r_(x), y, and r_(y) resultingin the following sets of equations:

$x = \frac{( {L_{x} - R_{x}} )( {d^{2} + {L_{x}R_{x}}} )}{2{d( {L_{x} + R_{x}} )}}$$r_{x} = {\frac{1}{2L}\sqrt{( {d^{2} - L_{x}^{2}} )^{2} + {4{x( {d + x} )}( {d^{2} - L_{x}^{2}} )}}}$$y = \frac{( {L_{y} - R_{y}} )( {d^{2} + {L_{y}R_{y}}} )}{2{d( {L_{y} + R_{y}} )}}$$r_{y} = {\frac{1}{2L}\sqrt{( {d^{2} - L_{y}^{2}} )^{2} + {4{y( {d + y} )}( {d^{2} - L_{y}^{2}} )}}}$

Once these values are determined, the z component may be determinedusing one of the following equations to provide the x, y, z coordinatesfor the location of the marker M relative to the distal end of theprobe. As with other embodiments described elsewhere herein, thisspatial relationship may then be presented on a display along with amodel of the body region within which the marker M is implanted.

z=√{square root over (r _(x) ² −y ²)}

z=√{square root over (r _(y) ² −x ²)}

FIGS. 17-20 present another approach for image generation utilizingmultiple distance measurements by a single antenna handpiece from a setof locations defined by an antenna placement template 1700. Antennaplacement template 1700 illustrates an embodiment wherein threemeasurement positions may be used to coordinate locations of multiplemeasurements taken by the probe to generate the model. Methods anddevices with additional measurement positions are likewise within thescope of this disclosure. For example, in some embodiments an antennaplacement template may have four, five, six, or more antenna placementpositions. In order to determine coordinates of the placed markers, theprobe may obtain measurements from multiple locations, such as thelocations correlating to the positions on the antenna placement template1700, and the system may use those measurements to calculate thecoordinates. If the locations of the measurements are known relative toeach other, three or more locations may be used for determining thecoordinates of the markers. A positioning rod 1708 may be used to placethe antenna placement template 1700.

The antenna placement template 1700 comprises three apertures (i.e., afirst aperture 1702, a second aperture 1704, a third aperture 1706)sized to receive a distal end of the probe. Each aperture is positionedat a known location relative to each other aperture. In the illustratedembodiment, the apertures are positioned in a triangular arrangement.The antenna placement template 1700 defines an XY plane for a coordinatesystem defining the locations of the markers.

The antenna placement template 1700 provides a template to use formeasurement locations. A probe with a single receive antenna may be usedto take measurements in those three apertures. A localization system mayuse these measurements to calculate distances and then ultimatelygenerate the coordinates of the each of the reflectors. Subsequently thesystem may create or display a three-dimensional image of the locationof the reflectors. Without the antenna placement template 1700 providingthe known locations, a system using a probe with a single antenna wouldlikely need additional points of measurements to determine thecoordinates of each of the reflectors.

FIG. 18 is a side view of an exemplary embodiment of a probe localizingfour markers 40 implanted within a breast 90. A physician using theantenna placement template 1700 would place the antenna placementtemplate 800 on a surface of the breast 90. The physician may thensequentially position a distal end of the probe 20 within each apertureof the antenna placement template 800.

While the probe is positioned at each aperture, the probe 20 maytransmit electromagnetic signals 34T and transmit light pulses 28 a intotissue contacted by the distal end of the probe 90. The probe mayreceive signals 34R reflected from the markers 40 implanted within thepatient's body. The probe 20 may be able to use a single receive antennato collect measurements at each aperture.

The localization system may use the reflected signals 34R to determinedistance values corresponding to distances from each of the plurality ofmarkers to the distal end of the probe 90 positioned at each aperture.For example, the localization system may process a first set ofmodulated reflected signals from the plurality of markers when probe isplaced in the first aperture to determine a first set of distance valuescorresponding to distances from each of the plurality of markers to thedistal end of the probe when in the first aperture. The system may alsoprocess a second set of modulated reflected signals from the pluralityof markers when probe is placed in the second aperture to determine asecond set of distance values corresponding to distances from each ofthe plurality of markers to the distal end of the probe when in thesecond aperture. And similarly, the system may process a third set ofmodulated reflected signals from the plurality of markers when probe isplaced in the third aperture to determine a third set of distance valuescorresponding to distances from each of the plurality of markers to thedistal end of the probe when in the third aperture.

In some embodiments, the localization system may transmitelectromagnetic signals may be emitted automatically when the probe isplaced in an aperture. In some embodiments, a button or switch will beused to initiate the transmission of electromagnetic signals. Thelocalization system may determine coordinates for each of the markersrelative to the antenna placement template based on the distance valuesas illustrated in FIGS. 19-20C.

For example, FIG. 19 represents a chart 1900 with three sets of distancevalues. In this embodiment, there are four markers implanted.Accordingly, each set of distance values includes four groups of samplesseparated into individual markers. As previously discussed, thelocalization system may identify these samples because each the markersmay include one or more features to facilitate identifying such asunique modulation of the reflected signal.

The samples are obtained sequentially at locations defined by theantenna placement template. In the illustrated embodiment, each setincludes multiple distance samples calculated based on the receivedreflected signals. A first set 1902 of distance values is obtained whilethe probe is at a first aperture of the antenna placement template.Similarly, a second set 1904 of distance values is obtained while theprobe is at a second aperture of the antenna placement template.Additionally, a third set 1906 of distance values is obtained while theprobe is at a third aperture of the antenna placement template.

The localization system may use these distance values to calculate thevalues coordinate table 1908. For example, for the case of athree-position template with equidistant placement, such as antennaplacement template 1700 of FIG. 17, the coordinates may be determinedusing the following equations.

${x = \frac{d_{1}^{2} - d_{2}^{2}}{2L}},{y = {\frac{1}{2\sqrt{3}L}\lbrack {{2L^{2}} + {2d_{3}^{2}} - ( {d_{2}^{2} + d_{1}^{2}} )} \rbrack}},{z = \sqrt{d_{3}^{2} - x^{2} - y^{2}}},$

where L is the distance between the centers of the antenna placements inthe template and d₁, d₂ and d₃ are distances measured between thereflector and corresponding antenna location.

FIGS. 20A-20C illustrate potential interfaces that may be used todisplay the coordinates for each marker. For example, these interfacesmay be shown on the display 38 a shown in FIG. 1. The coordinates may beused to show the markers from any angle. The illustrated examplesinclude a perspective view interface 2000, a tope view interface 2002,and a side view interface 2004. These may be shown individually on thedisplay or in combination. The “X” marks identify the location of wherethe probe took the distance measurements, and the circle marks representeach of the markers.

Additionally, in some embodiments, the localization system may generatea model comprising a three-dimensional representation of the body regionshowing the markers within the body region. For example, the perspectiveview interface 2000, the tope view interface 2002, or the side viewinterface 2004 may be overlaid on a model of the body region.

Additionally, in some embodiments, the localization system may have theability to track a location of the probe and adjust the orientation ofthe coordinates based on the probe location. For example, in someembodiments, the probe may include a gyroscope and an accelerometer totrack the location and orientation of the probe. As the localizationsystem changes position, the interface displayed may rotate to provide acorresponding view change. Any methods disclosed herein include one ormore steps or actions for performing the described method. The methodsteps and/or actions may be interchanged with one another. In otherwords, unless a specific order of steps or actions is required forproper operation of the embodiment, the order and/or use of specificsteps and/or actions may be modified. Moreover, sub-routines or only aportion of a method described herein may be a separate method within thescope of this disclosure. Stated otherwise, some methods may includeonly a portion of the steps described in a more detailed method.

Reference throughout this specification to an “embodiment” means that aparticular feature, structure, or characteristic described in connectionwith that embodiment is included in at least one embodiment. Thus,references to embodiments throughout this specification are notnecessarily all referring to the same embodiment.

Similarly, it should be appreciated by one of skill in the art with thebenefit of this disclosure that in the above description of embodiments,various features are sometimes grouped together in a single embodiment,figure, or description thereof for the purpose of streamlining thedisclosure. This method of disclosure, however, is not to be interpretedas reflecting an intention that any claim requires more features thanthose expressly recited in that claim. Rather, as the following claimsreflect, inventive aspects lie in a combination of fewer than allfeatures of any single foregoing disclosed embodiment. Thus, the claimsfollowing this Detailed Description are hereby expressly incorporatedinto this Detailed Description, with each claim standing on its own as aseparate embodiment. This disclosure includes all permutations of theindependent claims with their dependent claims.

Recitation in the claims of the term “first” with respect to a featureor element does not necessarily imply the existence of a second oradditional such feature or element. It will be apparent to those havingskill in the art that changes may be made to the details of theabove-described embodiments without departing from the underlyingprinciples of the present disclosure.

We claim:
 1. A system for localization of a region within a patient'sbody, comprising: a plurality of markers sized for implantation within aregion within a patient's body, each marker comprising: a) an energyconverter configured to transform light pulses into electrical energy;b) one or more elongate members coupled to a switch to provide one ormore antennas; and c) a circuit coupled to the energy converter andswitch to open and close the switch to modulate electromagnetic signalsreflected by the marker based at least in part on the light pulses; anda probe comprising: a) a housing comprising a distal end configured forplacement against a surface of the region towards the markers; b) one ormore antennas adjacent the distal end for transmitting electromagneticsignals into a patient's body and receiving reflected signals from thepatient's body; c) a light source for delivering light pulses into apatient's body synchronized with the electromagnetic signals whereuponthe markers modulate reflected signals from the respective markers; andd) a processor coupled to the one or more antennas configured to: i)process the modulated reflected signals from the markers at one or moreof the surface locations to determine marker locations within the regionto obtain a reference frame relative to the region; ii) determinedistance values corresponding to distances from the respective markersto the distal end at each of the surface locations; and iii) determinecoordinates of the surface locations relative to the reference frame togenerate a model of the body region.
 2. The system of claim 1, whereinthe processor is configured to acquire modulated reflected signals fromthe markers substantially simultaneously at each of the surfacelocations.
 3. The system of claim 2, wherein: the light source isconfigured to transmit the light pulses in spaced-apart frames includinga plurality of pulses for providing clock signals to the markers suchthat the markers modulate their reflective properties using orthogonalcode sequences triggered by the clock signals, wherein the processor isfurther configured for processing the reflected signals to separate themodulated reflected signals from the markers based at least in part onthe code sequences to identify and locate each of the plurality ofmarkers substantially simultaneously.
 4. The system of claim 1, whereinthe probe is configured to acquire modulated reflected signals from themarkers sequentially from each of the surface locations.
 5. The systemof claim 1, further comprising a display, and wherein the processor iscoupled to the display for presenting the model on the display.
 6. Thesystem of claim 5, wherein the model comprises a three-dimensionalrepresentation of the body region showing the markers within the bodyregion.
 7. The system of claim 5, wherein the processor is furtherconfigured for presenting a current location of the distal end relativeto the model on the display.
 8. The system of claim 1, wherein theelectromagnetic signals comprise a plurality of ultrawide band radarpulses generated in synchronization with the light pulses.
 9. A probefor localization of a region within a patient's body using a pluralityof markers implanted within the region, the probe comprising: a housingcomprising a distal end configured for placement against a surface ofthe region towards the markers; one or more antennas adjacent the distalend for transmitting electromagnetic signals into a patient's body andreceiving reflected signals from the patient's body; a light source fordelivering light pulses into a patient's body synchronized with theelectromagnetic signals whereupon the markers modulate reflected signalsfrom the respective markers; and a processor coupled to the one or moreantennas configured to: i) process the modulated reflected signals fromthe markers at one or more of the surface locations to determine markerlocations within the region to obtain a reference frame relative to theregion; ii) determine distance values corresponding to distances fromthe respective markers to the distal end at each of the surfacelocations; and iii) determine coordinates of the surface locationsrelative to the reference frame to generate a three dimensional model ofthe body region.
 10. The probe of claim 9, wherein the processor isconfigured to acquire modulated reflected signals from the markerssubstantially simultaneously at each of the surface locations.
 11. Theprobe of claim 10, wherein: the light source is configured to transmitthe light pulses in spaced-apart frames including a plurality of pulsesfor providing clock signals to the markers such that the markersmodulate their reflective properties using orthogonal code sequencestriggered by the clock signals, wherein the processor is furtherconfigured for processing the reflected signals to separate themodulated reflected signals from the markers based at least in part onthe code sequences to identify and locate each of the plurality ofmarkers substantially simultaneously.
 12. The probe of claim 9, whereinthe processor is configured to acquire modulated reflected signals fromthe markers sequentially from each of the surface locations.
 13. Theprobe of claim 9, further comprising a display, and wherein theprocessor is coupled to the display for presenting the model on thedisplay.
 14. The probe of claim 13, wherein the model comprises athree-dimensional representation of the body region showing the markerswithin the body region.
 15. The probe of claim 13, wherein the processoris further configured for presenting a current location of the distalend relative to the model on the display.
 16. The probe of claim 9,wherein the electromagnetic signals comprise a plurality of ultrawideband radar pulses generated in synchronization with the light pulses.17. A probe for localization of a region within a patient's body usingone or more markers implanted within the region, the probe comprising: ahousing comprising a distal end including a substrate configured forplacement against a surface of the region towards the markers; atransmit antenna on the substrate configured for transmittingelectromagnetic signals into a patient's body; a plurality of receiveantennas spaced apart from one another on the substrate, each configuredfor receiving reflected signals from the patient's body; a light sourcefor delivering light pulses distally from the substrate into a patient'sbody synchronized with the electromagnetic signals whereupon the one ormore markers modulate reflected signals from the one or more markers;and a processor coupled to the plurality of sets of receive antennasconfigured to process the modulated reflected signals from the one ormore markers to determine distance values corresponding to distancesfrom the one or more markers to respective sets of receive antennas, anddetermine coordinates defining the spatial location of the one or moremarkers relative to the distal end.
 18. The probe of claim 17, whereinthe processor is configured to use trilateration based on the distancesfrom a first marker of the one or more markers to the distal end toidentify the spatial location of the first marker in three-dimensions.19. The probe of claim 17, wherein the processor is configured toacquire modulated reflected signals from a plurality of markerssubstantially simultaneously, the processor further configured todetermine distance values corresponding to distances from each of theplurality of markers to respective sets of receive antennas based on themodulated reflected signals, and determine coordinates defining thespatial location of the each of the plurality of markers relative to thedistal end.
 20. The probe of claim 17, wherein the processor isconfigured to acquire modulated reflected signals from a plurality ofmarkers sequentially, the processor further configured to determinedistance values corresponding to distances from each of the plurality ofmarkers to respective sets of receive antennas based on the modulatedreflected signals, and determine coordinates defining the spatiallocation of the each of the plurality of markers relative to the distalend.